Partial fatty acid oxidation inhibitors in the treatment of congestive heart failure

ABSTRACT

Methods are disclosed for treating congestive heart failure with partial inhibitors of fatty acid oxidation. The compounds increase cardiac performance without affecting heart rate, blood pressure, or oxygen consumption.

BACKGROUND OF THE INVENTION

[0001] This application claims priority to U.S. Provisional ApplicationSerial No. 60/183560, filed Feb. 18, 2000, and U.S. ProvisionalApplication Serial No. 60/219908, filed Jul. 21, 2000 the specificationsof each of which are incorporated herein by reference.

FIELD OF THE INVENTION

[0002] This invention relates to a method of treating congestive heartfailure by increasing cardiac performance without increasing myocardialoxygen consumption. In particular, the invention relates to a method oftreating congestive heart failure with compounds that partially inhibitfatty acid oxidation. This invention also relates to pharmaceuticalformulations that maintain plasma concentrations of such compounds attherapeutically effective levels for extended periods of time.

BACKGROUND

[0003] Congestive heart failure (CHF) is a major cause of death anddisability in industrialized society. It is not a disease in itself, buta condition in which the heart is unable to pump an adequate supply ofblood to meet the oxygen requirements of the body's tissues and organs.As a result, fluid accumulates in the heart and other organs, such asthe lungs, and spreads into the surrounding tissues. CHF is often asymptom of cardiovascular problems such as coronary artery disease,myocardial infarction, cardiomyopathy, heart valve abnormalities, andthe like.

[0004] Conventionally, CEF has been treated with a wide variety ofdrugs, including alpha-adrenergic agonists, beta-adrenergic antagonists,calcium channel antagonists, cardiac glycosides, diuretics, nitrates,phosphodiesterase inhibitors, prazosin, and a variety of vasodilators.All of these drugs, however, have undesirable side-effects. For example,use of alpha-adrenergic agonists results in edema of the peripheraltissues. β-adrenergic agents are effective initially, but prolonged useleads to the progressive development of desensitization to the drug.Treatment with cardiac glycosides is well known to produce toxicside-effects in the CNS, and also the gastrointestinal and respiratorysystems. Cardiac glycosides additionally produce pro-arrhythmic effects.Treatment with diuretics may result in a variety of adverse-effects, themost severe of which include electrolyte abnormalities, such ashyponatremia, hypokalemia, and hyperchloremic metabolic alkalosis.

[0005] Other problems with current methods of treatment of CHF areexemplified by drugs such as calcium channel antagonists, such asverapamil, diltiazem and nifedipine. These agents initially also produceimprovement in the symptoms of CHF, but prolonged use of the agentsrender them ineffective. Moreover, calcium channel antagonists have beenshown to increase the mortality rates in patients thus treated, becausesuch compounds act to increase oxygen consumption, which furtherstresses the compromised heart.

[0006] CHF is characterized by progressive left contractile dysfunction.Accordingly, a desirable approach to treating CHF would be one thatenhances contractile function by increasing the efficiency of energyproduction in the heart thereby increasing cardiac output and mechanicalperformance.

[0007] In the normal heart, most of the energy for contractile functionis generated by two processes; 1) oxidative phosphorylation of fattyacids, and, to a lesser extent; 2) oxidation of lactate and glucose,although the latter process is the more efficient. However, in patientswith CHF, there is a concomitant increase in fatty acids so that theamount of energy obtained from the relatively inefficient metabolism offatty acids increases during exercise-induced stress, and the relativeamount of energy generated by the more efficient oxidation of glucoseand lactate is reduced. Consequently, the failing heart is furthercompromised by inefficient energy generation.

[0008] Therefore, there is a need for providing a method of treating CHFwith agents that switch substrate use in the heart from fatty acids toglucose/lactates, thus improving left ventricle function, withoutincreasing the myocardial oxygen requirement. It is also preferred thatthe drugs do not act directly to stimulate cardiac contractility, orproduce side-effects such as changes in blood pressure and/or heartrate, since they are associated with increased mortality in patientswith CHF.

[0009] U.S. Pat. No. 4,567,264, the specification of which isincorporated herein by reference, discloses compounds said to havecalcium entry blockade properties. In particular, one of thosecompounds,(±)-N-(2,6—dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-1-piperazineacetamide(known as ranolazine) is undergoing clinical trials for the treatment ofangina. Despite the drawbacks generally associated with calcium channelantagonists for the treatment of CHF, it has surprisingly beendiscovered that the compounds disclosed therein do not have thedisadvantages noted above. It has been found that the compounds of '264exert their beneficial effect as a consequence of having partial fattyacid oxidation (pFox) inhibiting properties, and that they are valuablefor the treatment of CHF. In particular, the compounds of the inventionswitch substrate use in the heart from fatty acids to glucose/lactates,thus improving left ventricle function, while not producing adverseside-effects such as changes in blood pressure and/or heart rate, and donot act directly to stimulate cardiac contractility, all of which wouldbe expected from a calcium entry blocker.

[0010] A problem with conventional pharmaceutical formulations ofcompounds of '264 is that they have low bioavailability, because thehigh acid solubility of the compounds results in rapid drug absorptionand clearance, causing large and undesirable fluctuations in plasmaconcentration. Also, such compounds have a short duration of action,thus necessitating frequent oral administration for adequate treatment.There is, therefore, a need for a method for administering the compoundsof '264, in particular ranolazine, in a dosage form that providessustained therapeutically effective plasma concentrations of ranolazinefor the treatment of congestive heart failure.

[0011] U.S. Pat. No. 5,506,229, which is incorporated herein byreference, discloses the use of ranolazine for the treatment of tissuesexperiencing a physical or chemical insult, including cardioplegia,hypoxic or reperfusion injury to cardiac or skeletal muscle or braintissue, and for use in transplants.

[0012] U.S. Pat. No. 5,472,707, the specification of which isincorporated herein by reference, discloses a high-dose oral formulationemploying supercooled liquid ranolazine as a fill solution for a hardgelatin capsule or softgel.

[0013] WO0013687, the specification of which is incorporated herein byreference, discloses a sustained release formulation of ranolazine foruse in the treatment of angina.

SUMMARY OF THE INVENTION

[0014] In a first aspect, the invention provides a method of treatingcongestive heart failure in mammals, comprising administering to amammal in need thereof a therapeutically effective amount of a compoundthat partially inhibits fatty acid oxidation, preferably without effectupon heart rate or blood pressure. Administration is preferably as abolus or a continuous infusion, or a combination of a bolus andcontinuous infusion, or as an orally active sustained releaseformulation.

[0015] In a second aspect, this invention provides a method of treatingcongestive heart failure in mammals, comprising administering to amammal in need thereof a partial fatty acid oxidation inhibitor ofFormula I:

[0016] wherein:

[0017] R¹, R², R³, R⁴ and R⁵ are each independently hydrogen, loweralkyl, lower alkoxy, cyano, trifluoromethyl, halo, lower alkylthio,lower alkyl sulfinyl, lower alkyl sulfonyl, or N-optionally substitutedalkylamido, provided that when R¹ is methyl, R⁴ is not methyl;

[0018] or R² and R³ together form —OCH₂O—;

[0019] R⁶, R⁷, R⁸, R⁹ and R¹⁰ are each independently hydrogen, loweracyl, aminocarbonylmethyl, cyano, lower alkyl, lower alkoxy,trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, loweralkyl sulfonyl, or di-lower alkyl amino; or

[0020] R⁶ and R⁷ together form —CH═CH—CH═CH—; or

[0021] R⁷ and R⁸ together form —O—CH₂ O—;

[0022] R¹¹ and R¹² are each independently hydrogen or lower alkyl; and

[0023] W is oxygen or sulfur;

[0024] and the pharmaceutically acceptable salts and esters thereof.

[0025] A preferred compound is namedN-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-1-piperazineacetamide,as a racemic mixture, or an isomer thereof.

[0026] In a third aspect, this invention provides a method of treatingcongestive heart failure in mammals, comprising intravenouslyadministering to a mammal in need thereof a therapeutically effectiveamount of a compound of Formula I, as a bolus or by continuous infusion,or a combination of both.

[0027] In a fourth aspect, this invention provides a method of treatingcongestive heart failure in mammals, comprising administering to amammal in need thereof a therapeutically effective amount of a compoundof Formula I, as a sustained release pharmaceutical composition,preferably orally.

[0028] In a fifth aspect, this invention provides a method of treatingcongestive heart failure in mammals, comprising administering to amammal in need thereof a compound of Formula I in a manner thatmaintains plasma concentrations of the compound at therapeutic levels.

[0029] In one preferred embodiment, the compound of Formula I isadministered by iv infusion in a manner that provides plasma level ofthe compound of Formula I of at least (0.35±0.03 ng/ml) 350±30 ng/nL forat least 12 hours.

[0030] In a second preferred embodiment, the compound of Formula I isadministered as a sustained release formulation that maintains plasmaconcentrations of the compound of Formula I at a maximum of 4000 ng/ml,preferably between about 850 to about 4000 ng base/mL, for at least 12hours.

DESCRIPTION OF THE FIGURES

[0031]FIG. 1 is a plot of exercise time in patients who wereadministered a placebo or varying amounts of ranolazine in a sustainedrelease dosage formulation. Data are expressed relative to the controlpatients treated with placebo.

DETAILED DESCRIPTION OF THE INVENTION Definitions and General Parameters

[0032] As used in the present specification, the following words andphrases are generally intended to have the meanings as set forth below,except to the extent that the context in which they are used indicatesotherwise.

[0033] “Aminocarbonylmethyl” refers to a group having the followingstructure:

[0034] where A represents the point of attachment.

[0035] “Halo” or “halogen” refers to fluoro, chloro, bromo or iodo.

[0036] “Lower acyl” refers to a group having the following structure:

[0037] where R, is lower alkyl as is defined herein, and A representsthe point of attachment, and includes such groups as acetyl, propanoyl,n-butanoyl and the like.

[0038] “Lower alkyl” refers to a unbranched saturated hydrocarbon chainof 1-4 carbons, such as methyl, ethyl, n-propyl, and n-butyl.

[0039] “Lower alkoxy” refers to a group—OR wherein R is lower alkyl asherein defined.

[0040] “Lower alkylthio” refers to a group—SR wherein R is lower alkylas herein defined.

[0041] “Lower alkyl sulfinyl” refers to a group of the formula:

[0042] wherein R is lower alkyl as herein defined, and A represents thepoint of attachment.

[0043] “Lower alkyl sulfonyl” refers to a group of the formula:

[0044] wherein R is lower alkyl as herein defined., and A represents thepoint of attachment.

[0045] “N-Optionally substituted alkylamido” refers to a group havingthe following structure:

[0046] wherein R is independently hydrogen or lower alkyl and R′ islower alkyl as defined herein, and A represents the point of attachment.

[0047] “Isomers” refers to compounds having the same atomic mass andatomic number but differing in one or more physical or chemicalproperties. All isomers of the compound of Formula I are within thescope of the invention.

[0048] “Optional” or “optionally” means that the subsequently describedevent or circumstance may or may not occur, and that the descriptionincludes instances where said event or circumstance occurs and instancesin which it does not.

[0049] The term “therapeutically effective amount” refers to that amountof a compound of Formula I that is sufficient to effect treatment, asdefined below, when administered to a mammal in need of such treatment.The therapeutically effective amount will vary depending upon thesubject and disease condition being treated, the weight and age of thesubject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art.

[0050] The term “treatment” or “treating” means any treatment of adisease in a mammal, including:

[0051] (i) preventing the disease, that is, causing the clinicalsymptoms of the disease not to develop;

[0052] (ii) inhibiting the disease, that is, arresting the developmentof clinical symptoms; and/or

[0053] (iii) relieving the disease, that is, causing the regression ofclinical symptoms.

[0054] In many cases, the compounds of this invention are capable offorming acid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto. The term “pharmaceuticallyacceptable salt” refers to salts that retain the biologicaleffectiveness and properties of the compounds of Formula I, and whichare not biologically or otherwise undesirable. Pharmaceuticallyacceptable base addition salts can be prepared from inorganic andorganic bases. Salts derived from inorganic bases, include by way ofexample only, sodium, potassium, lithium, ammonium, calcium andmagnesium salts. Salts derived from organic bases include, but are notlimited to, salts of primary, secondary and tertiary amines, such asalkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines,di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenylamines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines,di(substituted alkenyl) amines, tri(substituted alkenyl) amines,cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines,substituted cycloalkyl amines, disubstituted cycloalkyl amine,trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl)amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines,disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines,aryl amines, diaryl amines, triaryl amines, heteroaryl amines,diheteroaryl amines, triheteroaryl amines, heterocyclic amines,diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amineswhere at least two of the substituents on the amine are different andare selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic,and the like. Also included are amines where the two or threesubstituents, together with the amino nitrogen, form a heterocyclic orheteroaryl group.

[0055] “Partial fatty acid oxidation inhibitors” refers to compoundsthat suppress ATP production from the oxidation of fatty acids andconsequently stimulate ATP production from the oxidation of glucose andlactate. In the heart, most of the ATP production is acquired throughthe metabolism of fatty acids. The metabolism of glucose and lactateprovides a lesser proportion of ATP. However, the generation of ATP fromfatty acids is less efficient with respect to oxygen consumption thanthe generation of ATP from the oxidation of glucose and lactate. Thus,the use of pFox inhibitors results in more energy production permolecule of oxygen consumed, allowing the heart to be energized moreefficiently. PFox inhibitors are especially useful, therefore, in anischemic environment in which oxygen levels are reduced.

Pharmaceutical Compositions and Administration

[0056] The compounds of Formula I are usually administered in the formof pharmaceutical compositions. This invention therefore providespharmaceutical compositions that contain, as the active ingredient, oneor more of the compounds of Formula I, or a pharmaceutically acceptablesalt or ester thereof, and one or more pharmaceutically acceptableexcipients, carriers, including inert solid diluents and fillers,diluents, including sterile aqueous solution and various organicsolvents, permeation enhancers, solubilizers and adjuvants. Thecompounds of Formula I may be administered alone or in combination withother therapeutic agents. Such compositions are prepared in a mannerwell known in the pharmaceutical art (see, e.g., Remington'sPharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17^(th)Ed. (1985) and “Modem Pharmaceutics”, Marcel Dekker, Inc. 3^(rd) Ed. (G.S. Banker & C. T. Rhodes, Eds.).

[0057] The compounds of Formula I may be administered in either singleor multiple doses by any of the accepted modes of administration ofagents having similar utilities, for example as described in thosepatents and patent applications incorporated by reference, includingrectal, buccal, intranasal and transdermal routes, by intra-arterialinjection, intravenously, intraperitoneally, parenterally,intramuscularly, subcutaneously, orally, topically, as an inhalant, orvia an impregnated or coated device such as a stent, for example, or anartery-inserted cylindrical polymer.

[0058] One preferred mode for administration is parental, particularlyby injection. The forms in which the novel compositions of the presentinvention may be incorporated for administration by injection includeaqueous or oil suspensions, or emulsions, with sesame oil, corn oil,cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose,or a sterile aqueous solution, and similar pharmaceutical vehicles.Aqueous solutions in saline are also conventionally used for injection,but less preferred in the context of the present invention. Ethanol,glycerol, propylene glycol, liquid polyethylene glycol, and the like(and suitable mixtures thereof), cyclodextrin derivatives, and vegetableoils may also be employed. The proper fluidity can be maintained, forexample, by the use of a coating, such as lecithin, by the maintenanceof the required particle size in the case of dispersion and by the useof surfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, andthe like.

[0059] Sterile injectable solutions are prepared by incorporating thecompound of Formula I in the required amount in the appropriate solventwith various other ingredients as enumerated above, as required,followed by filtered sterilization. Generally, dispersions are preparedby incorporating the various sterilized active ingredients into asterile vehicle which contains the basic dispersion medium and therequired other ingredients from those enumerated above. In the case ofsterile powders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum-drying and freeze-dryingtechniques which yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

[0060] Compounds of Formula I may be impregnated into a stent bydiffusion, for example, or coated onto the stent such as in a gel form,for example, using procedures known to one of skill in the art in lightof the present disclosure.

[0061] Oral administration is another route for administration of thecompounds of Formula I. Administration may be via capsule or entericcoated tablets, or the like. In making the pharmaceutical compositionsthat include at least one compound of Formula I, the active ingredientis usually diluted by an excipient and/or enclosed within such a carrierthat can be in the form of a capsule, sachet, paper or other container.When the excipient serves as a diluent, in can be a solid, semi-solid,or liquid material (as above), which acts as a vehicle, carrier ormedium for the active ingredient. Thus, the compositions can be in theform of tablets, pills, powders, lozenges, sachets, cachets, elixirs,suspensions, emulsions, solutions, syrups, aerosols (as a solid or in aliquid medium), ointments containing, for example, up to 10% by weightof the active compound, soft and hard gelatin capsules, sterileinjectable solutions, and sterile packaged powders.

[0062] Some examples of suitable excipients include lactose, dextrose,sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate,alginates, tragacanth, gelatin, calcium silicate, microcrystallinecellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, andmethyl cellulose. The formulations can additionally include: lubricatingagents such as talc, magnesium stearate, and mineral oil; wettingagents; emulsifying and suspending agents; preserving agents such asmethyl- and propylhydroxy-benzoates; sweetening agents; and flavoringagents.

[0063] The preferred compositions of the invention are formulated so asto provide quick, sustained or delayed release of the active ingredientafter administration to the patient, especially sustained releaseformulations. The most preferred compound of the invention is ranolazinewhich is named (±)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2methoxyphenoxy) propyl]-1-piperazine-acetamide. Unless otherwise stated,the ranolazine plasma concentrations used in the specification andexamples refers to ranolazine free base.

[0064] Controlled release drug delivery systems for oral administrationinclude osmotic pump systems and dissolutional systems containingpolymer-coated reservoirs or drug-polymer matrix formulations. Examplesof controlled release systems are given in U.S. Pat. Nos. 3,845,770;4,326,525; 4,902514; and 5,616,345, and WO 0013687. Another formulationfor use in the methods of the present invention employs transdermaldelivery devices (“patches”). Such transdermal patches may be used toprovide continuous or discontinuous infusion of the compounds of thepresent invention in controlled amounts. The construction and use oftransdermal patches for the delivery of pharmaceutical agents is wellknown in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and5,001,139. Such patches may be constructed for continuous, pulsatile, oron demand delivery of pharmaceutical agents.

[0065] The compositions are preferably formulated in a unit dosage form.The term “unit dosage forms” refers to physically discrete unitssuitable as unitary dosages for human subjects and other mammals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect, in association with asuitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule). Itwill be understood, however, that the amount of the compound of FormulaI actually administered will be determined by a physician, in the lightof the relevant circumstances, including the condition to be treated,the chosen route of administration, the actual compound administered andits relative activity, the age, weight, and response of the individualpatient, the severity of the patient's symptoms, and the like.

[0066] For preparing solid compositions such as tablets, the principalactive ingredient is mixed with a pharmaceutical excipient to form asolid preformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules.

[0067] The tablets or pills of the present invention may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action, or to protect from the acid conditions of the stomach.For example, the tablet or pill can comprise an inner dosage and anouter dosage component, the latter being in the form of an envelope overthe former. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

[0068] Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices that deliver the formulationin an appropriate manner.

[0069] The the intraveous formulation of ranolazine is manufactured viaan aseptic fill process as follows. In a suitable vessel, the requiredamount of Dextrose Monohydrate is dissolved in Water for Injection (WFI)at approximately 78% of the final batch weight. With continuousstirring, the required amount of ranolazine free base is added to thedextrose solution. To facilitate the dissolution of ranolazine, thesolution pH is adjusted to a target of 3.88-3.92 with 0.1N or 1NHydrochloric Acid solution. Additionally, 0.1N HCl or 1.0N NaOH may beutilized to make the final adjustment of solution to the target pH of3.88-3.92. After ranolazine is dissolved, the batch is adjusted to thefinal weight with WFI. Upon confirmation that the in-processspecifications have been met, the ranolazine bulk solution is sterilizedby sterile filtration through two 0.2 μm sterile filters. Subsequently,the sterile ranolazine bulk solution is aseptically filled into sterileglass vials and aseptically stoppered with sterile stoppers. Thestoppered vials are then sealed with clean flip-top aluminum seals.

[0070] The sustained release formulations of this invention arepreferably in the form of a compressed tablet comprising an intimatemixture of compound and a partially neutralized pH-dependent binder thatcontrols the rate of dissolution in aqueous media across the range of pHin the stomach (typically approximately 2) and in the intestine(typically approximately about 5.5).

[0071] To provide for a sustained release of compound, one or morepH-dependent binders are chosen to control the dissolution profile ofthe compound so that the formulation releases the drug slowly andcontinuously as the formulation passed through the stomach andgastrointestinal tract. The dissolution control capacity of thepH-dependent binder(s) is particularly important in a sustained releaseformulation because a sustained release formulation that containssufficient compound for twice daily administration may cause untowardside effects if the compound is released too rapidly (“dose-dumping”).

[0072] Accordingly, the pH-dependent binders suitable for use in thisinvention are those which inhibit rapid release of drug from a tabletduring its residence in the stomach (where the pH is-below about 4.5),and which promotes the release of a therapeutic amount of compound fromthe dosage form in the lower gastrointestinal tract (where the pH isgenerally greater than about 4.5). Many materials known in thepharmaceutical art as “enteric” binders and coating agents have thedesired pH dissolution properties. These include phthalic acidderivatives such as the phthalic acid derivatives of vinyl polymers andcopolymers, hydroxyalkylcelluloses, alkylcelluloses, cellulose acetates,hydroxyalkylcellulose acetates, cellulose ethers, alkylcelluloseacetates, and the partial esters thereof, and polymers and copolymers oflower alkyl acrylic acids and lower alkyl acrylates, and the partialesters thereof

[0073] Preferred pH-dependent binder materials that can be used inconjunction with the compound to create a sustained release formulationare methacrylic acid copolymers. Methacrylic acid copolymers arecopolymers of methacrylic acid with neutral acrylate or methacrylateesters such as ethyl acrylate or methyl methacrylate. A most preferredcopolymer is methacrylic acid copolymer, Type C, USP (which is acopolymer of methacrylic acid and ethyl acrylate having between 46.0%and 50.6% methacrylic acid units). Such a copolymer is commerciallyavailable, from Röhm Pharma as Eudragit® L 100-55 (as a powder) orL30D-55 (as a 30% dispersion in water). Other pH-dependent bindermaterials which may be used alone or in combination in a sustainedrelease formulation dosage form include hydroxypropyl cellulosephthalate, hydroxypropyl methylcellulose phthalate, cellulose acetatephthalate, polyvinylacetate phthalate, polyvinylpyrrolidone phthalate,and the like. One or more pH-dependent binders are present in the dosageforms of this invention in an amount ranging from about 1 to about 20 wt%, more preferably from about 5 to about 12 wt % and most preferablyabout 10 wt %.

[0074] One or more pH-independent binders may be in used in sustainedrelease formulations in oral dosage forms. It is to be noted thatpH-dependent binders and viscosity enhancing agents such ashydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose,polyvinylpyrrolidone, neutral poly(meth)acrylate esters, and the like,do not themselves provide the required dissolution control provided bythe identified pH-dependent binders. The pH-independent binders arepresent in the formulation of this invention in an amount ranging fromabout 1 to about 10 wt %, and preferably in amount ranging from about 1to about 3 wt % and most preferably about 2.0 wt %.

[0075] As shown in Table 1, the preferred compound of the invention,ranolazine, is relatively insoluble in aqueous solutions having a pHabove about 6.5, while the solubility begins to increase dramaticallybelow about pH 6. TABLE 1 Solution pH Solubility (mg/mL) USP SolubilityClass  4.81 161 Freely Soluble  4.89 73.8 Soluble  4.90 76.4 Soluble 5.04 49.4 Soluble  5.35 16.7 Sparingly Soluble  5.82 5.48 Slightlysoluble  6.46 1.63 Slightly soluble  6.73 0.83 Very slightly soluble 7.08 0.39 Very slightly soluble  7.59 (unbuffered water) 0.24 Veryslightly soluble  7.79 0.17 Very slightly soluble 12.66 0.18 Veryslightly soluble

[0076] Increasing the pH-dependent binder content in the formulationdecreases the release rate of the sustained release form of the compoundfrom the formulation at pH is below 4.5 typical of the pH found in thestomach. The enteric coating formed by the binder is less soluble andincreases the relative release rate above pH 4.5, where the solubilityof compound is lower. A proper selection of the pH-dependent binderallows for a quicker release rate of the compound from the formulationabove pH 4.5, while greatly affecting the release rate at low pH.Partial neutralization of the binder facilitates the conversion of thebinder into a latex like film which forms around the individualgranules. Accordingly, the type and the quantity of the pH-dependentbinder and amount of the partial neutralization composition are chosento closely control the rate of dissolution of compound from theformulation.

[0077] The dosage forms of this invention should have a quantity ofpH-dependent binders sufficient to produce a sustained releaseformulation from which the release rate of the compound is controlledsuch that at low pHs (below about 4.5) the rate of dissolution issignificantly slowed. In the case of methacrylic acid copolymer, type C,USP (Eudragit® L 100-55), a suitable quantity of pH-dependent binder isbetween 5% and 15%. The pH dependent binder will typically have fromabout 1 to about 20% of the binder methacrylic acid carboxyl groupsneutralized. However, it is preferred that the degree of neutralizationranges from about 3 to 6%. The sustained release formulation may alsocontain pharmaceutical excipients intimately admixed with the compoundand the pH-dependent binder. Pharmaceutically acceptable excipients mayinclude, for example, pH-independent binders or film-forming agents suchas hydroxypropyl methylcellulose, hydroxypropyl cellulose,methylcellulose, polyvinylpyrrolidone, neutral poly(meth)acrylate esters(e.g. the methyl methacrylate/ethyl acrylate copolymers sold under thetrademark Eudragit® NE by Röhm Pharma, starch,gelatin, sugarscarboxymethyl cellulose, and the like. Other useful pharmaceuticalexcpients include diluents such as lactose, mannitol, dry starch,microcrystalline cellulose and the like; surface active agents such aspolyoxyethylene sorbitan esters, sorbitan esters and the like; andcoloring agents and flavoring agents. Lubricants (such as tale andmagnesium stearate) and other tableting aids are also optionallypresent.

[0078] The sustained release formulations of this invention have acompound content of above about 50% by weight to about 95% or more byweight, more preferably between about 70% to about 90% by weight andmost preferably from about 70 to about 80% by weight; a pH-dependentbinder content of between 5% and 40%, preferably between 5% and 25%, andmore preferably between 5% and 15%; with the remainder of the dosageform comprising pH-independent binders, fillers, and other optionalexcipients.

[0079] One particularly preferred sustained release formulations of thisinvention is shown below in Table 2. TABLE 2 Weight Preferred IngredientRange (%) Range (%) Most Preferred Active ingredient 0-95 70-90 75Microcrystalline cellulose (filler) 1-35  5-15 10.6 Methacrylic acidcopolymer 1-35   5-12.5 10.0 (Type C) Sodium hydroxide 0.1-1.0 0.2-0.60.4 Hydroxypropyl methylcellulose 0.5-5.0 1-3 2.0 Magnesium stearate0.5-5.0 1-3 2.0

[0080] The sustained release formulations of this invention are preparedas follows: compound and pH-dependent binder and any optional excipientsare intimately mixed(dry-blended). The dry-blended mixture is thengranulated in the presence of an aqueous solution of a strong base whichis sprayed into the blended powder. The granulate is dried, screened,mixed with optional lubricants (such as talc or magnesium stearate), andcompressed into tablets. Preferred aqueous solutions of strong bases aresolutions of alkali metal hydroxides, such as sodium or potassiumhydroxide, preferably sodium hydroxide, in water (optionally containingup to 25% of water-miscible solvents such as lower alcohols).

[0081] The resulting tablets may be coated with an optional film-formingagent, for identification, taste-masking purposes and to improve ease ofswallowing. The film forming agent will typically be present in anamount ranging from between 2% and 4% of the tablet weight. Suitablefilm-forming agents are well known to the art and include hydroxypropyl.methylcellulose, cationic methacrylate copolymers (dimethylaminoethylmethacrylate/methyl-butyl methacrylate copolymers—Eudragit® E—Röhm.Pharma), and the like. These film-forming agents may optionally containcolorants, plasticizers, and other supplemental ingredients.

[0082] The compressed tablets preferably have a hardness sufficient towithstand 8 Kp compression. The tablet size will depend primarily uponthe amount of compound in the tablet. The tablets will include from 300to 1100 mg of compound free base. Preferably, the tablets will includeamounts of compound free base ranging from 400-600 mg, 650-850 mg, and900-1100 mg.

[0083] In order to influence the dissolution rate, the time during whichthe compound containing powder is wet mixed is controlled. Preferablythe total powder mix time, i.e. the time during which the powder isexposed to sodium hydroxide solution, will range from 1 to 10 minutesand preferably from 2 to 5 minutes. Following granulation, the particlesare removed from the granulator and placed in a fluid bed dryer fordrying at about 60° C.

[0084] It has been found that these methods produce sustained releaseformulations that provide lower peak plasma levels and yet effectiveplasma concentrations of compound for up to 12 hours and more afteradministration, when the compound used as its free base, rather than asthe more pharmaceutically common dihydrochloride salt or as another saltor ester. The use of free base affords at least one advantage: Theproportion of compound in the tablet can be increased, since themolecular weight of the free base is only 85% that of thedihydrochloride. In this manner, delivery of an effective amount ofcompound is achieved while limiting the physical size of the dosageunit.

[0085] Another advantage of sustained release formulations of thisinvention is that they are prepared by a process that essentiallyinvolves only water as a solvent, and utilizes standard pharmaceuticalprocessing techniques and equipment.

[0086] The sustained release formulations of this invention can be usedfor treating congestive heart failure. It is most preferred that thesustained release dosage formulation be used as a treatment formammalian congestive heart failure and most preferably as a treatmentfor congestive heart failure in humans.

[0087] The oral sustained release dosage formulations of this inventionare administered one, twice; or three times in a 24 hour period in orderto maintain a plasma compound level above the threshold therapeuticlevel and below the maximally tolerated levels, of between about 550 and7500 ng base/mL in a patient. This corresponds to an amount of compoundranging from about 644 ng/mL to about 8782 ng/mL. Furthermore, thetiming of the oral ingestion of the sustained release formulation dosageforms should be controlled to insure that the plasma compound level doesnot exceed about 7500 ng base/mL and preferably so that the plasma leveldoes not exceed about 5000 ng base/mL an most preferably so that is doesnot exceed 3800 ng base/mL. In some instances it may be beneficial tolimit the peak plasma level to no more than about ng base/mL at the sametime, the plasma trough levels should preferably not fall below about1000 ng base/mL, and in some instances should not fall below 1700 ngbase/mL

[0088] In order to achieve the preferred plasma level of from about 1000to about 3800 ng base/mL, it is preferred that the oral dosage formsdescribed herein are administered once or twice daily. If the dosageforms are administered twice daily, then it is preferred that the oraldosage forms are administered at about twelve hour intervals.

[0089] In addition to formulating and administering oral sustainedrelease dosage forms of this invention in a manner that controls theplasma levels, it is also important to minimize the difference betweenpeak and trough plasma levels. The peak plasma levels are typicallyachieved at from about 30 minutes to eight hours or more after initiallyingesting the dosage form while trough plasma levels are achieve atabout the time of ingestion of the next scheduled dosage form. It ispreferred that the sustained release dosage forms of this invention areadministered in a manner that allows for a peak active ingredient levelno more than 8 times greater than the trough level, preferably no morethan 4 times greater than the trough and most preferably no greater than2 times trough level.

[0090] The sustained release formulations of this invention provide thetherapeutic advantage of minimizing variations in plasma concentrationwhile permitting, at most, twice-daily administration. The formulationmay be administered alone, or (at least initially) in combination withan immediate release formulation if rapid achievement of atherapeutically effective plasma concentration is desired or by solubleIV formulations and oral dosage form.

[0091] The following Examples are representative of the invention, butare not to be construed as limiting the scope of the claims.

EXAMPLES

[0092] Throughout these Examples it should be noted that:

[0093] (1) Oral doses of the instant release (IR) formulation were givenas capsules or tablets of the dihydrochloride salt and are expressed asthe dihydrochloride salt.

[0094] (2) Oral doses of the sustained release (SR) formulation weregiven as tablets of the active ingredient base and are expressed as thefree base.

[0095] (3) When IR and SR formulations were compared in the same study,doses are expressed in terms of both base and dihydrochloride. Theconversion factor for dihydrochloride to base is 0.854 (e.g.: 400 mgdihydrochloride x 0.854=342 mg free base equivalent).

[0096] (4) All plasma levels and pharmacokinetic parameters areexpressed as levels of free base.

[0097] Definitons of other terms used in this application are:

[0098] ANOVA=analysis of variance

[0099] ATP=adenosine triphosphate

[0100] AUC_(x)=area under the curve after x hours or time interval

[0101] bid=twice daily

[0102] C_(max)=maximum concentration

[0103] C_(trough)=residual concentration at 8 hours post-dose for IRformulations and 12 hours post-dose for SR formulations A-C of Example2.

[0104] C_(x)=concentration at time x

[0105] ECG=electrocardiographic

[0106] ETT=exercise treadmill test

[0107] LV=left ventricle

[0108] Pbo=placebo

[0109] PDH=pyruvate dehydrogenase

[0110] tid=three times per day

[0111] T_(max)=time to maximum concentration

[0112] It should be noted that the Examples that follow illustrate thepreparation and use of representative formulations containing a compoundof Formula I, as exemplified by ranolazine.

Example 1

[0113] The intravenous formulation of ranolazine is manufactured via anaseptic fill process as follows. In a suitable vessel, the requiredamount of Dextrose Monohydrate is dissolved in Water for Injection (WFI)at approximately 78% of the final batch weight. With continuousstirring, the required amount of ranolazine free base is added to thedextrose solution. To facilitate the dissolution of ranolazine, thesolution pH is adjusted to a target of 3.88-3.92 with 0.1N or 1NHydrochloric Acid solution. Additionally, 0.N HCl or 1.0N NaOH may beutilized to make the final adjustment of solution to the target pH of3.88-3.92. After ranolazine is dissolved, the batch is adjusted to thefinal weight with WFI. Upon confirmation that the in-processspecifications have been met, the ranolazine bulk solution is sterilizedby sterile filtration through two 0.2 μm sterile filters. Subsequently,the sterile ranolazine bulk solution is aseptically filled into sterileglass vials and aseptically stoppered with sterile stoppers. Thestoppered vials are then sealed with clean flip-top aluminum seals.

Example 2

[0114] This Example describes a method of preparing immediate release(IR) ranolazine formulations. Ranolazine dihydrochloride (4000 g),microcrystalline cellulose (650 g), polyvinylpyrrolidone (100 g), andcroscarmellose sodium (100 g) powders were intimately mixed together ina Fielder PMA 65 mixer-granulator, and sufficient water was then added,with mixing to form a granulate. The granulate was dried in an AeromaticStrea-5 fluid bed drier, screened, and mixed with magnesium stearate(100 g). The mixture was filled into hard gelatin capsules to a fillweight of, for example, 500 mg per capsule to achieve a dose of 400 mgof ranolazine dihydrochloride (equivalent to 342 mg of ranolazine freebase) per capsule, but may be filled to fill weight of 30 to 400 mg ofranolazine dihydrochloride.

Example 3

[0115] This Example describes a method of preparing sustained release(SR) ranolazine formulations. A sustained release (SR) formulation,designated as SR Formulation A, and includingpH-dependent andpH-independent binders was prepared by combining Ranolazine (2500g),methacrylic acid copolymer, Type C (Eudragit® L 100-55—Röhm Pharma)(1000 g), microcrystalline cellulose (Avicel® (100 g) (710 g), andpolyvinyl pyrrolidinone powders were intimately mixed together in aFielder PMA 65 mixer-granulator. The mixture was granulated with asolution of sodium hydroxide (40 g) in water, and a 30% aqueousdispersion of methyl methacrylate/ethyl acrylate copolymer (Eudragit® NE30 D—Röhm Pharma) (1667 g) was added to the wet mass. The resultinggranulate was dried in an Aeromatic Strea-5 fluid bed drier, screened,and then mixed with croscarmellose sodium (100 g) and magnesium stearate(50 g). The mixture was compressed into 684 mg tablets with a Manesty Btablet press to achieve dose of 342 mg of ranolazine free base pertablet. This formulation is referred to as SR Formulation A. SRFormulation B was prepared in the same manner as SR Formulation A exceptthat the Eudragit® L 100-55 was reduced to 500 g, and the Eudragit® NE30 D was replaced by a 40% aqueous dispersion of a methylmethacrylate/ethyl acrylate copolymer (Eudragit® NE 40 D—Röhm Pharma)(2500 g). The resulting (SR) formulation included 342 mg ranolazine freebase per tablet.

[0116] In SR Formulation C, ranolazine free base (342 mgs) was blendedwith microcrystalline cellulose and polyvinyl pyrrolininone K25,granulated with water, dried, and blended with croscarmellose sodium andmagnesium stearate. The blend was compressed into tablets and coatedwith an enteric coating.

[0117] SR Formulation D, including only a pH dependent binder wasprepared by combining Ranolazine (7500 g), Eudragit® L 100-55 (1000 g),hydroxypropyl methylcellulose (Methocel® E5—source) (200 g), andmicrocrysalline cellulose (Avicel®) (1060 g) by intimate mixing. Themixed powders were granulated with a solution of sodium hydroxide (40 g)in water (1900 to 2500 grams). The granulate was dried and screened,mixed with magnesium stearate (200 g), and compressed for example intotablets weighing 667 mg to achieve a dose of 500 mg of ranolazine freebase per tablet. The tablets were spray coated in a 24 inch Accelacota®cylindrical pan coater with OPADRY film coating solution to a 2-4%weight gain. OPADRY film coating solutions are available in a variety ofcolors from Colorcon, West Point, Pa. The stepwise procedure forpreparing SR Formulation D is as follows:

[0118] a) Blend together ranolazine, microcrystalline cellulose,methacrylate copolymer (Type C and hydroxypropyl methyl cellulose usingan appropriate blender.

[0119] b) Dissolve sodium hydroxide in purified water.

[0120] c) Using appropriate granulation equipment, slowly add the sodiumhydroxide solution to the blend with constant mixing. Add a furtheraliquot of water, if necessary.

[0121] d) Continue mixing to achieve additional massing. Add a furtheraliquot of water, if necessary.

[0122] e) Dry granulated in a fluid bed dryer.

[0123] f) Screen dried granules through an appropriate mill.

[0124] g) Add magnesium stearate to the screened granules and blendtogether. Pass the granulated material through a chilsonator, if needed.

[0125] j) Disperse OPADRY powder in water and film-coat usingappropriately sized coating

[0126] i) Compress the granules into tablets using appropriately sizedtooling. equipment to a typical level of 2-4% by weight.

[0127] Polish with camauba wax using a typical level of 0.002-0.003% byweight.

Example 4

[0128] 1. In Vitro Comparison of IR Formulation and SR Formulations

[0129] The IR Formulation prepared according to Example 2 and the SRFormulations prepared according to Examples 2A-2C were tested in a USPApparatus 2 dissolution tester, using 900 mL of 0.M hydrochloric acid asthe dissolution fluid to simulate dissolution in the stomach. TABLE 3Percentage of Formulation Dissolved Formulation Time (hours) IR A B C0.25  88.1 0.5 100.5 13.9 17.6 17.5 1 101.7 19.9 26.0 25.7 2 27.8 47.535.9 4 39.0 69.2 48.4 8 52.4 90.1 64.7 12 61.6 99.6 74.2 24 80.8 105.6 95.4

[0130] The tabular results (Table 3) show that while the IR Formulationis completely dissolved in no more than 0.5 hours (as expected for animmediate release formulation), SR Formulations A, B, and C displayed aprolonged dissolution of a low pH, as is desirable for a sustainedrelease formulation.

[0131] II. In Vivo Comparison of IR Formulation and SR Formulations A,B, and C

[0132] Single doses of the IR Formulation prepared according to Example2 and SR Formulations A and B prepared according to Example 3 wereadministered to eleven healthy volunteers and their plasmaconcentrations of ranolazine free base were measured at 0, 20, 40, 60,90, and 120 minutes, hourly to six hours, twice-hourly to eighteenhours, and at twenty-four hours after administration (SR Formulationsonly). The results are set forth in Table 4 below. TABLE 4 Formulation .. . IR A B C C _(max) (ISD) (ng/mL) 1940(807) 753(264) 657(316) 925(747)C_(trough)(ISD)(ng/ml 165(111) 158(114) 182(110) 290(163) T_(max) (ISD)(hours) 1.27(0.5) 4.09(1.14) 4.05(1.31) 6.55(2.93) AUC₀₋₂₄ (ISD) 65305640 5280 5820 (ng.hr/mL)

[0133] From Table 4 it is apparent that SR Formulations A, B and C ofthis invention exhibit dissolution properties which make them suitablefor twice daily administration of ranolazine.

Example 5

[0134] This Example details a single-ascending dose, crossover-designstudy that assessed the safety and pharmacokinetic profile of singleoral dose of ranolazine base SR Formulation of Example 3D. Humansubjects were divided into three groups. Group 1 received 500, 750 and1000 mg ranolazine SR. Group 2 received 1250 and 1750 mg ranolazine SR.Group 3 received 1500 and 2000 mg ranolazine SR. Each group also had arandomized placebo phase. Mean pharmacokinetic parameters followingsingle oral doses of the ranolazine SR does are detailed in Table 5below: TABLE 5 Mean ± SD Pharmacokinetic Parameters (n = 8 except* n =7) C_(trough) AUC_(0-30rh) Dose SR (mg) Group C_(max) (ng/mL) (ng/mL) T_(max) (hr) (ng.hr/mL)  500 1  883 ± 353  382 ± 251 4.63 ± 1.19  9830 ±4250  750 1 1300 ± 1060  455 ± 353 4.25 ± 0.886 12500 ± 9000 1000  1*1610 ± 959  695 ± 438 5.71 ± 2.14 18100 ± 9630 1250 2 2210 ± 716  943 ±541 6.21 ± 3.52 25000 ± 8090 1500 3 1980 ± 1050 1070 ± 754 4.75 ± 0.88625400 ± 16000 1750 2 3670 ± 1570 2400 ± 1260 5.25 ± 2.31 49200 ± 182002000 3 2440 ± 1120 1640 ± 937 5.21 ± 2.30 35400 ± 19100

[0135] The pharmacokinetic results reported in Table 5 indicate thatranolazine was slowly released from the SR formulation, and consequentlythe absorption of ranolazine was dissolution-rate limited. This resultedin prolonged plasma drug concentration-time profiles observed at alldose levels, with peak plasma levels at 4 to 6 hours post dose. Over thedose range 500 to 2000 mg, the mean C_(max) and AUC_(0-30hr) increasedin an approximately dose-proportional manner, although there appeared tobe some deviation from proportionality Group 2.

Example 6

[0136] This Example details a double-blind, placebo-controlled, multipleascending-dose, crossover-designed volunteer study, to evaluate biddosing. Six subjects received 4 days dosing with ranolazine SRformulation prepared according to Example 2D at 500, 750, and 1000 mgbid, followed by a morning dose on Day 5. Pharmacokinetic results arereported in Table 6, below. TABLE 6 Day 5 Ranolazine PharmacokineticParameters (mean ± SD) Ranolazine SR Ranolazine SR Ranolazine SRParameter 500 mg bid (n = 7) 750 mg bid (n = 7) 1000 mg bid (n = 7)C_(max) (ng/mL) 1760 ± 715   2710 ± 657 3660 ± 1090 T_(max) (hr) 2.00 ±1.15  4.33 ± 1.62  4.17 ± 2.48 C_(min) (ng/mL) 585 ± 340 1260 ± 501 1960± 812

[0137] According to Table 6, ranolazine was slowly released from the SRformulation, and consequently the pharmacokinetics were dissolution-ratelimited. This resulted in extended plasma drug concentration-timeprofiles at all dose levels, with peak plasma levels observed at 2 to 4hours post dose.

[0138] These results indicate that useful ranolazine plasma levels canbe achieved in humans with dosing of this SR formulation on a bidschedule.

Example 7

[0139] This Example evaluated the safety and tolerability ofadministering racemic ranolazine free base formulations as in Example3D. The individual and mean concentrations of racemic ranolazine and itsenantiomers, (R)-(+)-N-(2.6-dimethylphenyl)-4-[2-hydroxy-3-(2methoxyphenoxy)-propyl]-1-piperazineacetamide,(S)-(−)-N-(2,6-dimethylphenyl)-4-[2hydroxy-3-(2-methoxyphenoxy)-propyl]-1-piperazineacetamide in humanplasma were also determined.

[0140] The study was performed with ascending doses of sustained releaseranolazine dosage forms. Before and at intervals during and after thedosing period, blood samples were drawn for ranolazine assay and bloodpressure, heart rate, ECG and symptoms were monitored throughout. Datasummaries were reviewed after each phase before proceeding to the nextphase of the study. Eight subjects, all healthy male volunteers agedbetween 18 and 40 entered and all completed the study and were availablefor pharmacokinetic and safety analysis. The subjects were each givendoses of the various types of ranolazine free base in the form ofsustained release tablets including 500 mg and 750 mg tablets or withmatching placebo as necessary (2×750 mg size plus 1×500 mg size) to makeunit oral doses of 1500 and 2000 mg.

[0141] In each phase: one dose bid for four days with a single dose onDay 5. On day 5 each volunteer underwent a fill pharmacokinetic profileincluding supine and erect blood pressure (BP) and heart rate, ECG data,adverse events, clinical chemistry and hematology results, urinalysisresults.

[0142] Steady state was tested for in each dose level, using C_(48h),C_(72h) and C_(96h) and log transformed data, by analysis of covarianceand by testing whether the coefficient for time was significantlydifferent (defined as p<0.05) from 0. These tests were made usingtwo-sided t-tests with estimates of variability from the ANOVA models.Steady state was also assessed by comparing means for C_(48h), C_(72h)and C_(96h) using a mixed effects ANOVA model and untransformed and log,transformed data. For hemodynamic parameters, Day 1 pre-dose treatmentmeans and Day 5 data were compared across treatments via two-sidedt-tests using estimates of variability from mixed effects ANOVA models.Ninety and 95% confidence intervals were calculated for the treatmentcomparisons. No adjustments were made for multiple comparisons.

[0143] The mean and standard deviation day 5 pharmacokinetic parametersof ranolazine free base are detailed in Table 7 below and the meanplasma profiles are shown in the figure. Steady-state plasma levels ofranolazine free base appeared to be attained by day 4. Within the doseinterval there was a slow rise to maximum levels with t_(max) valuesranging from 1 to 6 h post-dose. Thereafter levels declined slowly,producing a small degree of fluctuation in plasma levels over the dosinginterval. There appeared to be no differences in the pharmacokineticparameters of the (+) R and (−) S enantiomers of ranolazine followingmultiple dosing with this SR formulation. TABLE 7 Day 5 Racemic (RS),(+)R and (−)S Ranolazine SR Pharmacokinetic Parameters 1500 mg SR bid2000 mg SR bid Parameter RS ranolazine (+)R ranolazine (−)S ranolazineRS ranolazine C_(max) (ng/ml) 5284 ± 2434 2909 ± 1308 2944 ± 1426 7281 ±2700 C_(min) (ng/ml) 2932 ± 1918 1436 ± 1046 1514 ± 1201 4149 ± 2228Median t_(max) (h) 4.00 4.00 4.00 4.00 C_(96h) (ng/ml) 3656 ± 1918 2009± 1137 2399 ± 1205 5042 ± 1797 C_(108h) (ng/ml) 2942 ± 1937 1447 ± 10711541 ± 1260 4398 ± 2396 AUC_(96-108h) 49516 ± 23945 25731 ± 13385 26407± 14849 68459 ± 25842 (ng.h/ml) C_(ave) (ng/ml) 4126 ± 1995 2144 ± 11152201 ± 1237 5705 ± 2153 Degree of 0.664 ± 0.336 0.833 ± 0.402 0.824 ±0.443 0.591 ± 0.240 fluctuation

Example 8

[0144] This example demonstrates that sustained-release (SR)formulations can keep plasma levels in a therapeutic range with biddosing, and that such rherapeutic ranges are effective in treating CHF,as evidenced by the improved exercise duration times.

[0145] Patients, with or without congestive heart failure were withdrawnfrom anti-anginal drugs with reproducible anginalimited exerciseduration and >1 mm ST depression were randomized to Ran (500 mg bid,1000 mg bit and 1500 mg bid) and matching placebo (Pbo) in adouble-blind, four-period, Latin square crossover design. Exercisetreadmill tolerance testing (ETT) was performed following a modifiedBruce protocol, at trough (12 hr after dosing) and peak (4 hr afterdosing) dosing times. Table 8 shows the results. TABLE 8 Placebo 500 mgbid 1000 mg bid 1500 mg bid trough peak trough peak trough peak troughpeak Exercise 511 504 533 532 545 555 559 561 Duration (sec) p-value vs.placebo — —  0.003 <0.001 <0.001 <0.001 <0.001 <0.001 Time to Angina 412418 437 452 457 474 472 487 (sec) p-value vs. placebo — —  0.005 <0.001<0.001 <0.001 <0.001 <0.001 Time to 1 mm ST 448 442 470 479 491 502 514508 Depression (sec) p-value vs. placebo — — <0.001 <0.001 <0.001 <0.001<0.001 <0.001

[0146] Ranolazine improved exercise duration times in comparison to theplacebo. Plasma peak and trough concentrations are reported in Table 9below. Ran had no clinically meaningful effects vs. Pbo on rest orexercise blood pressure or heart rate. TABLE 9 Ranolazine PlasmaConcentration (Mean (± standard deviation) Dose 500 mg BID 1000 Mg BID1500 mg BID Peak (ng/mL) 1122(727) 2461 (1525) 3935(2084) Trough (ng/mL) 846(651) 1949(1425) 3266(1973)

Example 10

[0147] The following example shows the results of a dose definitionstudy in which patients were given ranolazine SR in doses of 500 mg bid,1000 mg bid, 1500 mg bid and placebo. The four treatments wereadministered in a double-blind fashion and in a random order fortreatment periods of one week's duration. At the end of each week ofdouble blind treatment patients underwent exercise testing just prior todosing (“trough”) and 4 hours after dosing, at the expected time of peakplasma levels (“peak”).

[0148] A plot of exercise time in patients who were administered aplacebo or varying amounts of ranolazine in a sustained release dosageformulation. Data are shown in FIG. 1 and are expressed relative to thecontrol patients treated with placebo.

Example 11

[0149] The following example is an in vivo model designed to test effectof formulations of ranolazine on congestive heart failure.

[0150] The efficacy of ranolazine was studied using a canine model ofcongestive heart failure. Chronic LV dysfunction and failure wasproduced by multiple sequential intracoronary embolizations withpolystyrene Latex microspheres (70-102 μm in diameter) which results inloss of viable myocardium. In the present study, 13 healthy mongrel dogsweighing between 23 and 25 kg underwent coronary microembolizations toproduce heart failure. Intracoronary microembolizations were performedduring cardiac catheterization under general anesthesia and sterileconditions. The anesthesia regimen consisted of intravenous oxymorphonehydrochloride (0.22 mg/kg), diazepam (0.17 mg/kg) and sodiumpentobarbital (150-250 mg to effect). Dogs underwent an average of 5microembolization procedures performed 1 to 3 weeks apart. Embolizationswere discontinued when LV ejection fraction, determinedangiographically, was <30%. Dogs were maintained for a period of 2-3weeks to ensure that infarctions produced by the last microembolizationwere completely healed before studies were initiated. An additionalgroup of 8 healthy normal dogs that did not undergo anymicroembolizations, were also studied so that the hemodynamic effects ofranolazine in the setting of normal physiology could be ascertained.(.The study was approved by the Henry Ford Health System Care ofExperimental Animals Committee and conformed to the “Position of theAmerican Heart Association on Research Animal Use,” adopted by theAssociation in November 1984, and to the Guiding Principles of theAmerican Physiological Society on use of research animals).

[0151] On the day of the study and following general anesthesia, aorticand LV pressure were measured with a catheter-tip micromanometer (MillarInstruments, Houston, Tex.) positioned through a femoral arteriotomy.Single-plane left ventriculograms were obtained during eachcatheterization after completion of the hemodynamic measurements withthe dog placed on its right side. Ventriculograms were recorded on 35 mmcine film at 30 frames per second during the injection of 20 ml ofcontrast material (Reno-M-60, Squib, Princeton, N.J.). Correction forimage magnification was made with a calibrated radiopaque grid placed atthe level of the LV. Left ventricular end-systolic and end-diastolicvolumes were calculated from ventricular silhouettes using thearea-length method. The LV ejection fraction was calculated as the ratioof the difference of end-diastolic volume and end-systolic volume toend-diastolic volume times 100. Stroke volume was calculated as thedifference between LV end-systolic and end-diastolic volumes obtainedfrom the ventriculogram. Cardiac output was calculated as the product ofstroke volume and heart rate. Extra systolic and post-extra systolicbeats were excluded from all analyses.

[0152] In each normal or heart failure dog, ranolazine dihydrochloridewas administered in saline as an intravenous bolus injection of 0.5mg/kg followed by a continuous intravenous infusion of 1.0 mg/kg/hr for40 min. Arterial blood samples were drawn for determination of plasmaranolazine concentration. Samples were obtained at 5, 10, 20, 30, 35 and40 min after initiation of treatment. Ranolazine was measured by highperformance liquid chromatography (HPLC) using mass spectral detection.Following the withdrawal of the final blood sample at 40 min,hemodynamic and angiographic measurements were repeated.

[0153] Each animal served as its own control. Pre-treatment values werecompared to post-treatment values using a two-tailed paired Student'st-test with significance set at p<0.05. Data are presented as the mean±standard error of the mean.

Results

[0154] Arterial ranolazine levels stablized by 10 minutes following thebolus injection (Table 10). The average ranolazine concentration duringthe final 10 minutes of treatment was 0.30±0.02 ng/mL in normal dogs and0.33±0.04 ng/mL in dogs with heart failure.

[0155] Intravenous administration of ranolazine had no significanteffects on heart rate or mean aortic pressure. Ranolazine improved LVsystolic function as evidenced by a significant increase in LV ejectionfraction, LV peak+dP/dt and LV stroke volume. Ranolazine also improveddiastolic function, as evidenced by an increase in LV peak−dP/dt (datanot shown).

What is claimed is:
 1. A method for treating congestive heart failure ina mammal, which method comprises administering to a mammal in need ofsuch treatment a therapeutically effective amount of a compound thatpartially inhibits fatty acid oxidation.
 2. The method of claim 1 ,wherein said compound is administered at a dose sufficient to provide aplasma level that inhibits partial fatty acid oxidation without havingan effect on heart rate or blood pressure.
 3. The method of claim 2 ,wherein administration of said compound is by a bolus, a continuousinfusion, or a combination of bolus and continuous infusion.
 4. Themethod of claim 3 , wherein the compound is administered as a solutionin dextrose monohydrate at a pH between 3.88 and 3.92.
 5. The method ofclaim 4 , wherein the composition is delivered as a bolus injection of0.5 mg/ml.
 6. The method of claim 4 , wherein the composition isdelivered by continuous infusion of 1.0 mg/kg/hr for 40 minutes.
 7. Themethod of claim 3 , wherein the compound is administered by both a bolusand continuous infusion.
 8. The method of claim 7 , wherein the bolusinjection is a dosage of 0.5 mg/ml and the intravenous injection is 1.0mg/kg/hr for 40 minutes.
 9. The method of claim 8 , wherein the plasmalevels are maintained at 350±30 ng/ml.
 10. The method of claim 2 ,wherein said compound is administered as an orally active sustainedrelease formulation.
 11. The method of claim 10 , wherein the sustainedrelease formulation is a composition comprising; Component CompositionRanolazine 75.0% Microcrystalline Cellulose 10.6% Methacrylate Copolymer10.0% (Type C) Sodium Hydroxide  0.4% Hydroxypropyl Methyl  2.0%Cellulose Magnesium Stearate  2.0%


12. The method of claim 11 , wherein the sustained release formulationis administered orally in tablet form once, twice or three times over a12 hour period.
 13. The method of claim 11 , wherein the effectiveplasma level attained by the sustained release formulation is sustainedfor at least 12 hours.
 14. The method of claim 11 , wherein theeffective plasma level attained by the sustained release formulation isbetween about 850 to 5000 ug/ml.
 15. The method of claim 11 , whereinthe effective plasma level attained by the sustained release formulationis between about 1000 to 4000 ug/ml.
 16. The method of claim 1 , whereinthe mammal is a human.
 17. The method of claim 1 , wherein the inhibitorof partial fatty acid oxidation is a compound of Formula I:

wherein: R¹, R², R³, R⁴ and R⁵ are each independently hydrogen, loweralkyl, lower alkoxy, cyano, trifluoromethyl, halo, lower alkylthio,lower alkyl sulfinyl, lower alkyl sulfonyl, or N-optionally substitutedalkylamido, or R² and R³ together form —OCH₂O—; R⁶, R⁷, R⁸, R⁹ and R¹⁰are each independently hydrogen, lower acyl, aminocarbonylmethyl, cyano,lower alkyl, lower alkoxy, trifluoromethyl, halo, lower alkylthio, loweralkyl sulfinyl, lower alkyl sulfonyl, or di-lower alkyl amino; or R⁶ andR⁷ together form —CH—CH—CH—CH—; or R⁷ and R⁸ together form —O—CH₂O—; R¹¹and R¹² are each independently hydrogen or lower alkyl; and W is oxygenor sulfur; or a pharmaceutically acceptable salt or ester thereof. 18.The method of claim 17 , wherein R¹, R², R³, R⁴, and R⁵ are hydrogen orlower alkyl R⁶, R⁷, R⁸, R⁹, and R¹⁰ are hydrogen, lower alkyl, or loweralkoxy, and R¹¹ and R¹² are hydrogen.
 19. The method of claim 18 ,wherein R², R³, R⁴, R⁷, R⁸, R⁹, and R¹⁰ are hydrogen, R¹, and R⁵ arelower alkyl, and R⁶ is lower alkoxy.
 20. The method of claim 19 ,wherein R¹ and R⁵ are both methyl, and R⁶ is methoxy, namely.(±)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-1-piperazineacetamide.21. The method of claim 20 , wherein said compound is administered at adose sufficient to provide a plasma level that inhibits partial fattyacid oxidation without having an effect on heart rate or blood pressure.22. The method of claim 21 , wherein administration of said compound isby a bolus or a continuous infusion, or a combination of a bolus andcontinuous infusion.
 23. The method of claim 22 , wherein the compoundis administered as a solution in dextrose monohydrate at a pH between3.88 and 3.92.
 24. The method of claim 22 , wherein the composition isadministered as a bolus injection of 0.5 mg/ml.
 25. The method of claim22 , wherein the composition is administered by continuous infusion of1.0 mg/kg/hr for 40 minutes.
 26. The method of claim 22 , wherein thecompound is administered by both a bolus and continuous infusion. 27.The method of claim 26 , wherein the bolus injection is a dosage of 0.5mg/ml and the intravenous injection is 1.0 mg/kg/hr for 40 minutes. 28.The method of claim 22 , wherein the plasma levels are maintained at350±30 ng/ml.
 29. The method of claim 20 , wherein said compound isadministered as an orally active sustained release formulation.
 30. Themethod of claim 29 , wherein the sustained release formulation is acomposition comprising; Component Composition Ranolazine 75.0%Microcrystalline Cellulose 10.6% Methacrylate Copolymer 10.0% (Type C)Sodium Hydroxide  0.4% Hydroxypropyl Methyl  2.0% Cellulose MagnesiumStearate  2.0%


31. The method of claim 30 , wherein the sustained release formulationis administered orally in tablet form once, twice or three times over a12 hour period.
 32. The method of claim 30 , wherein the effectiveplasma level attained by the sustained release formulation is sustainedfor at least 12 hours.
 33. The method of claim 30 , wherein theeffective plasma level attained by the sustained release formulation isbetween about 850 to 5000 ug/ml.
 34. The method of claim 33 , whereinthe effective plasma level attained by the sustained release formulationis between about 1000 to 4000 ug/ml.
 35. The method of claim 20 ,wherein the mammal is a human.